Abstract Collectively lymphoid cancers are the 5th most common cancer in North America, with the majority being aggressive B-cell lymphomas. Despite modern treatment, it is recognized that defined groups of patients continue to experience high rates of treatment failure and poor outcomes. These groups comprise (a) the ABC molecular subtype of diffuse large B-cell lymphoma (DLBCL), (b) high grade tumors especially those harboring the MYC translocation (particularly in combination with BCL2 translocation) and (c) lymphomas that involve certain extranodal sites. Merely intensifying therapy does not overcome this treatment resistance ? novel approaches are required. Over the past decade, we defined the biology of ABC DLBCL, allowing identification of cell vulnerabilities (?Achilles heels?) exploitable using novel targeted agents and developed clinical grade assays that robustly identify the disease and are currently supporting phase 3 clinical trials of these precision medicine approaches. There is a paucity of knowledge regarding the biology underlying the other treatment resistant aggressive B-cell lymphomas. Based on the blueprint provided by our success with ABC DLBCL, we hypothesize that a systematic examination of the genomic landscape of these understudied entities will provide the basis for improved outcomes by (a) identifying key common targetable cellular vulnerabilities and pathways providing the basis for precision medicine and (b) allowing development of accurate assays to identify this targetable biology and support these novel approaches. In Specific Aim 1 we will determine the incidence and architecture of MYC rearrangements across the aggressive B-cell lymphoma entities using fluorescence in situ hybridization and a novel capture sequencing approach. Specific Aim 2 is to determine the genetic underpinnings of aggressive B-cell lymphomas. Whole exome sequencing, RNAseq and OncoScan (for copy number alterations) will be performed on High grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (?double-? and ?triple-hit? lymphoma (200 cases)), High grade B-cell lymphoma not otherwise specified (100), plasmablastic lymphoma (50) and extranodal DLBCL (200). Integrative bioinformatics approaches (Biostatistics and Bioinformatics Core) will be applied to identify common targetable pathway perturbations and new Achilles Heels. Specific Aim 3 is to develop biomarkers that inform patient treatment decision. In a first step, knock-out screens of ?double hit? cell lines will be performed (Functional Genomics Core) allowing integration with findings from Specific Aim 2 to prioritize key tumor vulnerabilities. Therapeutic strategies tested in these cell lines will be taken forward for preclinical testing in mouse models (Preclinical Models and Therapeutic Core). Then diagnostic and predictive biomarker assays will be developed to support clinical trials and patient management. Our consortium, with its vast tumor repository, world-leading pathology expertise (Pathology Core) and outstanding track record in translational medicine, is uniquely positioned to perform this critical research paving the way to improved outcomes through precision medicine.